Metabolic syndrome has become a global epidemic that significantly increases the risk for type 2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease (NAFLD). While hepatic steatosis often exists as a benign condition, a subset of NAFLD patients develop non-alcoholic steatohepatitic (NASH), which is characterized by progressive liver injury, inflammation, and fibrosis. The regulatory networks that control hepatic lipid metabolism have been a focus of research in the past two decades. These studies provide critical insights into the molecular and physiological mechanisms that contribute to the pathogenesis of hepatic steatosis. However, our understanding of the pathogenic mechanisms that drive the development of NASH from benign steatosis is remarkably limited. Further, a lack of appropriate animal models that recapitulate key aspects of NASH limits our ability to define the underlying pathogenic events and to evaluate their potential value in therapeutic development. Recent studies have shown that liver autophagy is impaired in insulin resistant states and its deficiency contributes to hepatic steatosis. The fundamental role of autophagy in hepatic lipid metabolism and liver function remains poorly understood. Here, we discovered a new molecular pathway that regulates the program of autophagy gene expression and autophagy in hepatocytes. Based on a body of new preliminary data, we hypothesize that impaired autophagy in the liver perturbs hepatic lipid metabolism and exacerbates liver injury, inflammation, and fibrosis. In this proposal, we will first define the molecular mechanisms that regulate autophagy in hepatocytes. We will assess the role of autophagy in lipid metabolism using a mouse strain with conditional autophagy deficiency in the liver. Finally, we will use genetic and chemical approaches to evaluate whether activation of autophagy improves hepatic lipid homeostasis and ameliorates the progression of NASH pathologies. Successful completion of this project will provide novel insights into the fundamental crosstalk between autophagy and lipid metabolic pathways, and shift the current paradigm on the pathogenesis of NASH. PUBLIC HEALTH RELEVANCE: Non-alcoholic fatty liver disease (NAFLD) is emerging as a major risk factor for end- stage liver disease and there is an urgent unmet medical need for its diagnosis and treatment. Here we discovered a new mechanism that links autophagy to hepatic lipid metabolism and liver disease. We proposed to use state-of- the-art molecular, genetic, and metabolic tools to establish the significance of this new pathway in the pathogenesis of NAFLD.